Trial Of NS2359 For The Treatment of Cocaine Dependence

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT02798627
• Collaborator: Saniona (Industry), The Dana Foundation (Other)
• Enrollment: 55
• Location: 1
• Arms: 2
• Duration (Months): 53
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

NS2359 attenuates the euphoria associated with cocaine use. In a manner parallel to cocaine, NS2359 blocks the reuptake of dopamine (DA), norepinephrine (NE), and serotonin (5HT) with nanomolar affinities at the 3 transporters. In primates NS2359 significantly attenuated cocaine self-administration. In several phase II clinical trials for major depressive disorder and adult attention deficit disorder, NS2359 did not cause euphoria. NS2359 exhibited no abuse potential in a human laboratory study comparing NS2359 with amphetamine. In a phase I human laboratory interaction study, NS2359 showed no toxicity after 20 or 40 mg of cocaine, but it attenuated the both the rewarding and cardiovascular effects of intravenous cocaine. On the basis of these promising studies, investigators propose a Phase II double-blind clinical trial of NS2359 in cocaine addiction (CA). The proposed trial will involve 100 CA subjects participating in an eight week trial, including a 1-week baseline and 8 weeks of NS2359 or placebo treatment. Four weeks after completing the medication phase, there will be one follow-up visit. Subjects will be randomly assigned to treatment with placebo or 2 mg NS2359 daily, with a possible decrease to 1 mg daily for adverse events. This dose range is selected on the basis of phase I and II evidence of tolerability and NS2359 plasma levels which were associated with blockade of cocaine reward. This project has the potential to identify the first effective pharmacotherapy for CA.

Condition or Disease	Intervention/Treatment	Phase
Cocaine Use Disorder	Drug: NS2359; Drug: placebo	Phase 2

Detailed Description

In this phase II randomized double-blind, placebo-controlled trial, 40 persons will be randomized to NS2359 and 40 to placebo. The primary hypothesis is: more NS2359-treated subjects (compared to placebo-treated subjects) will achieve 3 consecutive weeks of cocaine abstinence, as measured by urine benzoylecgonine (BE) assay, during the last three weeks of the trial. The study is 9 weeks: one week of screening, followed by an 8-week double-blind, placebo-controlled trial. All subjects will receive weekly cognitive behavioral therapy (CBT) to encourage abstinence during their 3 times weekly clinic visits. Investigators expect ~ 20% dropout rate, based on our recent CA clinical trials (eg, Kampman et al, 2015 and 2013), so 80 randomized patients will yield ~ 64 study completers. There will be a 1 month start-up period, followed by 20 months of recruitment for the study. The 1 month start-up period will allow for training of staff, preparation of study capsules, placement of study advertisements, etc. Penn IRB approval has been obtained. There will be a 2-month termination period to allow the final patients to complete the study. Data cleaning, statistical analyses and preparation of reports will be done in the final two months. Based on recent cocaine pharmacotherapy trials conducted by our team, monthly enrollment of ~4 CA participants (respondents to flyers and advertisements) is feasible.

Recruitment will occur at the University of Pennsylvania's Treatment Research Center (TRC), led by Kyle Kampman, MD, and Wade Berrettini, MD, PhD, Professors of Psychiatry at Penn. At the TRC, CA patients are respondents to advertisements for free treatment of CA. The ethnicity is 90% African-American, 9 % European-American, 70% male, mean age 47 (+/- 12).

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Double-Blind, Placebo-Controlled, Trial Of NS2359 For The Treatment of Cocaine Dependence
• Study Start Date: May 1, 2016
• Actual Primary Completion Date: Mar 1, 2020
• Actual Study Completion Date: Oct 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NS2359 The initial dose of the NS2359 will be two mg once daily. Patients with difficult adverse events at the 2 mg dose will be allowed to reduce to 1 mg once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9.	Drug: NS2359; NS2359 is a small molecule which inhibits the reuptake of dopamine, norepinephrine and serotonin with equal affinity.
Placebo Comparator: placebo Placebo pills matched to NS2359 pills will be given once daily. Patients with difficult adverse events at the 2 mg placebo will be allowed to reduce to 1 mg placebo once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9.	Drug: placebo; Placebo pills identical in appearance to the NS2359 will be provided

Outcome Measures

Primary Outcome Measures

1. The Number of Participants Who Achieved Abstinence From Cocaine During the Last Three Weeks of the Trial [8 weeks]

   Number of Participants Who Report no Cocaine Use and Have no Cocaine Positive Urine Drug Screens in the NS2359 Group Versus the Placebo Group Comparator During the Last Three Weeks of the Trial [ Time Frame: weeks 6,7.8 of the trial ] Number of subjects with cocaine abstinence as measured through three-times-weekly urine benzoylecgonine (BE) levels in urine drug screen (UDS) and self-reports of use from the Time Line Follow Back. UDS results and TLFB reports combined to yield weekly use/no-use indicators for each week of treatment.

Secondary Outcome Measures

1. Average Weekly Cocaine Craving Scores NS2359 Group Versus the Placebo Group Comparator [ Time Frame: Once Per Week in Weeks 2 Through 8 ] [8 weeks]

   As measured by average weekly scores for cocaine craving on the brief substance craving scale combining cocaine craving frequency, intensity and duration. Minimum value 0 maximum value 12 higher scores indicate worse craving.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male and females, 18-65 years old.

2. Meets diagnostic criteria (DSM-V) for current diagnosis of cocaine use disorder, moderate to severe, by semi-structured interview.

3. In the past 30 days, used no less than $100-worth of cocaine

4. Speaks, understands, and prints in English.

Exclusion Criteria:

1. Meets DSM-V criteria for substance use disorder, moderate to severe, for a substance other than cocaine, alcohol or nicotine. Subjects with comorbid alcohol use disorder will be accepted if their alcohol use disorder is not severe enough to require a medical alcohol detoxification.

2. Needs treatment with any psychoactive medications (with the exception of diphenhydramine or melatonin, if necessary, for sleep).

3. Meets current or lifetime DSM-V criteria for schizophrenia or any psychotic disorder, or organic mental disorder.

4. Has another Axis I psychiatric disorder that in the opinion of the physician will interfere with completion of the study or place the patient at heightened risk through participation in the trial.

5. Has evidence of a history of significant hematological, pulmonary, endocrine, cardiovascular, renal or gastrointestinal disease.

6. Use of an investigational medication in the 30 days prior to randomization.

7. Is female and has a positive pregnancy test, is contemplating pregnancy in the next 6 months, is nursing, or is not using effective contraception (if relevant).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania
• Saniona
• The Dana Foundation

Investigators

• Principal Investigator: Wade Berrettini, MD, PhD, University of Pennsylvania Perelman School of Medicine, Department of Psychiatry

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 2, 2019

More Information

Publications

None provided.

• Responsible Party: Kyle Kampman, Professor of Psychiatry, University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT02798627
• Other Study ID Numbers: 824109
• First Posted: Jun 14, 2016
• Last Update Posted: May 24, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Cocaine-Related Disorders

Study Results

Participant Flow

Recruitment Details	Recruitment by advertising in local newspapers and radio began in 07/2016 and ended in 12/2018.
Pre-assignment Detail	Participants had a screening telephone appointment to determine eligibility. If eligible, they were seen at the clinic for history, physical exam and urine drug screen. A positive urine drug screen for a cocaine metabolite (BE) was used as a stratifying variable in randomization.

Arm/Group Title	NS2359	Placebo
Arm/Group Description	The initial dose of the NS2359 will be two mg once daily. Patients with difficult adverse events at the 2 mg dose will be allowed to reduce to 1 mg once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9. NS2359: NS2359 is a small molecule which inhibits the reuptake of dopamine, norepinephrine and serotonin with equal affinity.	Placebo pills matched to NS2359 pills will be given once daily. Patients with difficult adverse events at the 2 mg placebo will be allowed to reduce to 1 mg placebo once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9. placebo: Placebo pills identical in appearance to the NS2359 will be provided
Period Title: Overall Study
STARTED	27	28
COMPLETED	27	28
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	NS2359	Placebo	Total
Arm/Group Description	The initial dose of the NS2359 will be two mg once daily. Patients with difficult adverse events at the 2 mg dose will be allowed to reduce to 1 mg once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9. NS2359: NS2359 is a small molecule which inhibits the reuptake of dopamine, norepinephrine and serotonin with equal affinity.	Placebo pills matched to NS2359 pills will be given once daily. Patients with difficult adverse events at the 2 mg placebo will be allowed to reduce to 1 mg placebo once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9. placebo: Placebo pills identical in appearance to the NS2359 will be provided	Total of all reporting groups
Overall Participants	27	28	55
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	56.4	52	53.8
Sex: Female, Male (Count of Participants)
Female	3 11.1%	5 17.9%	8 14.5%
Male	24 88.9%	23 82.1%	47 85.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	24 88.9%	26 92.9%	50 90.9%
White	3 11.1%	2 7.1%	5 9.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	27 100%	28 100%	55 100%
Days of cocaine use in past 30 (Days) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Days]	9.0	9.5	9.0

Outcome Measures

1. Primary Outcome

Title	The Number of Participants Who Achieved Abstinence From Cocaine During the Last Three Weeks of the Trial
Description	Number of Participants Who Report no Cocaine Use and Have no Cocaine Positive Urine Drug Screens in the NS2359 Group Versus the Placebo Group Comparator During the Last Three Weeks of the Trial [ Time Frame: weeks 6,7.8 of the trial ] Number of subjects with cocaine abstinence as measured through three-times-weekly urine benzoylecgonine (BE) levels in urine drug screen (UDS) and self-reports of use from the Time Line Follow Back. UDS results and TLFB reports combined to yield weekly use/no-use indicators for each week of treatment.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NS2359	Placebo
Arm/Group Description	The initial dose of the NS2359 will be two mg once daily. Patients with difficult adverse events at the 2 mg dose will be allowed to reduce to 1 mg once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9. NS2359: NS2359 is a small molecule which inhibits the reuptake of dopamine, norepinephrine and serotonin with equal affinity.	Placebo pills matched to NS2359 pills will be given once daily. Patients with difficult adverse events at the 2 mg placebo will be allowed to reduce to 1 mg placebo once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9. placebo: Placebo pills identical in appearance to the NS2359 will be provided
Measure Participants	27	28
Number [participants]	2 7.4%	2 7.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NS2359, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.97
	Comments
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Average Weekly Cocaine Craving Scores NS2359 Group Versus the Placebo Group Comparator [ Time Frame: Once Per Week in Weeks 2 Through 8 ]
Description	As measured by average weekly scores for cocaine craving on the brief substance craving scale combining cocaine craving frequency, intensity and duration. Minimum value 0 maximum value 12 higher scores indicate worse craving.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NS2359	Placebo
Arm/Group Description	The initial dose of the NS2359 will be two mg once daily. Patients with difficult adverse events at the 2 mg dose will be allowed to reduce to 1 mg once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9. NS2359: NS2359 is a small molecule which inhibits the reuptake of dopamine, norepinephrine and serotonin with equal affinity.	Placebo pills matched to NS2359 pills will be given once daily. Patients with difficult adverse events at the 2 mg placebo will be allowed to reduce to 1 mg placebo once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9. placebo: Placebo pills identical in appearance to the NS2359 will be provided
Measure Participants	27	28
Mean (Standard Error) [score on a scale]	4.09 (0.39)	3.89 (0.33)

Adverse Events

Time Frame	Adverse event data was measured over 12 weeks
Adverse Event Reporting Description	Patients completed adverse event forms and answered specific questions about adverse events
Arm/Group Title	NS2359		Placebo
Arm/Group Description	The initial dose of the NS2359 will be two mg once daily. Patients with difficult adverse events at the 2 mg dose will be allowed to reduce to 1 mg once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9. NS2359: NS2359 is a small molecule which inhibits the reuptake of dopamine, norepinephrine and serotonin with equal affinity.		Placebo pills matched to NS2359 pills will be given once daily. Patients with difficult adverse events at the 2 mg placebo will be allowed to reduce to 1 mg placebo once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9. placebo: Placebo pills identical in appearance to the NS2359 will be provided
All Cause Mortality
	NS2359		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/28 (0%)
Serious Adverse Events
	NS2359		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	NS2359		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/27 (40.7%)		1/28 (3.6%)
Cardiac disorders
Tachycardia	3/27 (11.1%)	3	0/28 (0%)	0
Gastrointestinal disorders
flatulence	2/27 (7.4%)	2	1/28 (3.6%)	1
Nervous system disorders
sedation	3/27 (11.1%)	3	0/28 (0%)	0
Vascular disorders
increased blood pressure	3/27 (11.1%)	3	0/28 (0%)	0

Limitations/Caveats

Small numbers of individuals analyzed. Some noncompliance per plasma NS2359 levels at mid and end treatment.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.